ABSTRACT This is an application for a Mentored Patient-Oriented Research Career Development Award (K23) for Dr. Julio C. Rojas, Assistant Adjunct Professor of Neurology at the University of California, San Francisco (UCSF) Memory and Aging Center. Dr. Rojas is committed to pursue a career in the field of fluid biomarkers for neurodegenerative diseases. The goals of this K23 application relevant to Dr. Rojas' career development are: (1) to gain research expertise in the analysis, interpretation and application of proteomics data for biomarker discovery in frontotemporal dementia; (2) to become proficient in the research methodology required to validate and deploy fluid biomarker data to support observational and interventional research in frontotemporal dementia; and (3) to develop a career path as an independent researcher. The aim of this project is to identify and validate fluid biomarkers in frontotemporal dementia (FTD), a group of conditions difficult to typify in vivo, due to limited clinicopathologic correlations. Dr. Rojas will combine a series of unprecedented resources to conduct an unbiased screen of the cerebrospinal fluid and plasma human proteomes to identify single molecular targets, molecular profiles or disruptions in cellular pathways of value as diagnostic or prognostic biomarkers or surrogate markers of therapy response in patients with FTD. Biomarker discovery will be done with parallel implementation of two innovative proteomics methodologies with complementary sensitivity and specificity, including an aptamer-based platform and mass spectrometry of post- translational modifications. This unique discovery effort will be conducted in pathology-confirmed cases of frontotemporal lobar degeneration, autosomal dominant FTD-causing mutation carriers, recruited through an international collaborative FTD research network, and participants of FTD clinical trials. Targets will be validated with biofluids immunoassay-based single-analyte measurements and immunohistochemistry of pathological specimens, and deployed to test their clinical utility in longitudinally characterized cohorts. This project addresses the critical need to identify clinically useful biomarkers in neurodegenerative diseases. Dr. Rojas is an ideal candidate for a K23 award. He will operate in the outstanding UCSF academic research environment, which will allow him to exploit his proven capacity for collaborative work, high scientific productivity and guidance from world-class scientists with successful mentoring tracks. Dr. Adam L. Boxer, a renowned expert in clinical trials will act as primary mentor to supervise the clinical application of fluid biomarkers. Dr. Nevan Krogan, a world leader in quantitative sciences, will act as co-mentor to supervise the analysis and interpretation of proteomics data. Drs. Isabel Allen and Lea Grinberg will collaborate with statistical analyses and neuropathology validation experiments. This project will launch Dr. Rojas' career as an independent clinician scientist and will prepare him to adopt a leadership role in the search for better diagnostic tests and treatments to help mitigate the increasing burden imposed by neurodegenerative diseases.